The PPM1D (WIP1) gene is overexpressed in over 50% of medulloblastomas and in 3 of the 4 recently described medulloblastoma molecular subgroups. Our preliminary data shows that WIP1 overexpression is also associated with tumor metastasis and poor progression-free and overall survival. The long-term goal of this application is to identify mechanisms and predictors of tumor progression and metastasis in order to develop therapies that will improve the survival of patients with WIP1-overexpressing medulloblastoma. We have found that WIP1 overexpressing medulloblastomas exhibit a unique cross-talk with Sonic Hedgehog (SHH) signaling and the chemokine G-protein-coupled receptor CXCR4 that is poorly characterized. Our central hypothesis is that WIP1 overexpression alters expression or activation of components of the SHH signaling cascade and results in aberrant localization or activation of CXCR4, causing increased growth, invasion, and metastasis of WIP1-overexpressing medulloblastoma cells. Using an innovative multidisciplinary approach that combines genetics and pharmacology, we will determine (1) the mechanisms of cross-talk between SHH and WIP1 signaling in MB tumorigenesis, (2) the mechanisms of MB invasion mediated by WIP1, and (3) the efficacy of targeting WIP1 along with agents that target SHH and CXCR4 signaling in mouse models of medulloblastoma to improve the treatment of aggressive medulloblastomas. Access to multiple models of WIP1 overexpression and multiple human medulloblastoma tissue sets places us in a unique position to discover novel therapeutic targets. Ultimately, this study will benefit human health by identifying new molecular targets and novel drug combinations in WIP1-overexpressing medulloblastomas. Understanding the molecular mechanisms associated with WIP1 overexpression will ultimately lead to improved, less toxic therapeutic strategies and improved survival rates in children diagnosed with brain cancer.